ClinVar Genomic variation as it relates to human health
NM_001330078.2(NRXN1):c.2533C>T (p.His845Tyr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(11); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001330078.2(NRXN1):c.2533C>T (p.His845Tyr)
Variation ID: 206245 Accession: VCV000206245.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 50497679 (GRCh38) [ NCBI UCSC ] 2: 50724817 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Apr 15, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001330078.2:c.2533C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001317007.1:p.His845Tyr missense NM_001135659.3:c.2653C>T NP_001129131.1:p.His885Tyr missense NM_001330077.2:c.2509C>T NP_001317006.1:p.His837Tyr missense NM_001330082.2:c.2509C>T NP_001317011.1:p.His837Tyr missense NM_001330083.2:c.2467C>T NP_001317012.1:p.His823Tyr missense NM_001330084.2:c.2467C>T NP_001317013.1:p.His823Tyr missense NM_001330085.2:c.2506C>T NP_001317014.1:p.His836Tyr missense NM_001330086.2:c.2533C>T NP_001317015.1:p.His845Tyr missense NM_001330087.2:c.2422C>T NP_001317016.1:p.His808Tyr missense NM_001330088.2:c.2452C>T NP_001317017.1:p.His818Tyr missense NM_001330093.2:c.2530C>T NP_001317022.1:p.His844Tyr missense NM_001330094.2:c.2521C>T NP_001317023.1:p.His841Tyr missense NM_001330095.2:c.2482C>T NP_001317024.1:p.His828Tyr missense NM_001330096.2:c.2422C>T NP_001317025.1:p.His808Tyr missense NM_004801.6:c.2533C>T NP_004792.1:p.His845Tyr missense NC_000002.12:g.50497679G>A NC_000002.11:g.50724817G>A NG_011878.1:g.539858C>T - Protein change
- H885Y, H818Y, H828Y, H836Y, H841Y, H844Y, H808Y, H845Y, H823Y, H837Y
- Other names
- p.H885Y:CAT>TAT
- p.His885Tyr
- Canonical SPDI
- NC_000002.12:50497678:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00099
The Genome Aggregation Database (gnomAD) 0.00064
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00056
Exome Aggregation Consortium (ExAC) 0.00060
1000 Genomes Project 30x 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00051
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NRXN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2274 | 2339 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Sep 22, 2015 | RCV000188275.15 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 22, 2024 | RCV000465496.29 | |
Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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May 31, 2023 | RCV000513409.30 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2021 | RCV000764442.13 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 28, 2019 | RCV002314734.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Sep 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000596082.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Uncertain significance
(Dec 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000704629.2
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Chromosome 2p16.3 deletion syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895499.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001302024.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001529580.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(May 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002541828.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
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Uncertain significance
(Mar 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000847536.4
First in ClinVar: Nov 08, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.H885Y variant (also known as c.2653C>T), located in coding exon 14 of the NRXN1 gene, results from a C to T substitution at nucleotide … (more)
The p.H885Y variant (also known as c.2653C>T), located in coding exon 14 of the NRXN1 gene, results from a C to T substitution at nucleotide position 2653. The histidine at codon 885 is replaced by tyrosine, an amino acid with similar properties. This variant has been reported in an individual with autism spectrum disorder (ASD) and his sibling with learning disabilities; however, the alteration was inherited from their unaffected father and no second variant in the NRXN1 gene was identified in this family (Jiang YH et al. Am. J. Hum. Genet., 2013 Aug;93:249-63). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Chromosome 2p16.3 deletion syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002495880.2
First in ClinVar: Apr 08, 2022 Last updated: May 06, 2023 |
Comment:
NRXN1 NM_001135659.2 exon 15 p.His885Tyr (c.2653C>T): This variant has been reported in the literature in at least 1 individual with autism spectrum disorder (ASD), segregating … (more)
NRXN1 NM_001135659.2 exon 15 p.His885Tyr (c.2653C>T): This variant has been reported in the literature in at least 1 individual with autism spectrum disorder (ASD), segregating with disease in 1 affected family member. However, this family member did not meet clinical criteria for ASD (Jiang 2013 PMID:23849776). This variant is present in 0.1% (78/68024) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-50497679-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:20245). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Uncertain significance
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000241886.13
First in ClinVar: Aug 07, 2015 Last updated: Jul 16, 2023 |
Comment:
Reported in a patient with autism spectrum disorder, sibling with learning disabilities and their unaffected father, and in an unrelated individual with spastic paraplegia and … (more)
Reported in a patient with autism spectrum disorder, sibling with learning disabilities and their unaffected father, and in an unrelated individual with spastic paraplegia and epilepsy who was also a compound heterozygote for 2 variants in the ALDH18A1 gene (Jiang et al., 2013; Steenhof et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 23849776, 29754261, 34168285) (less)
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Uncertain significance
(Jun 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003814163.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000552204.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jun 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608937.25
First in ClinVar: Oct 30, 2017 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963022.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966872.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Pitt-Hopkins-like syndrome 2
Chromosome 2p16.3 deletion syndrome
Affected status: unknown
Allele origin:
unknown
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GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies
Accession: SCV002047665.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant interpreted as Uncertain significance and reported on 07-13-2019 by lab or GTR ID 26957. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly … (more)
Variant interpreted as Uncertain significance and reported on 07-13-2019 by lab or GTR ID 26957. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of the nervous system (present) , Seizure (present) , Anxiety (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-07-13
Testing laboratory interpretation: Uncertain significance
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. | Jiang YH | American journal of human genetics | 2013 | PMID: 23849776 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NRXN1 | - | - | - | - |
Text-mined citations for rs199784139 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.